Amorphous form of cabazitaxel and process for its preparation

ABSTRACT

An Amorphous Form of Cabazitaxel is disclosed. It is preferably characterized by an X-ray powder diffraction (XRD) pattern as depicted in FIG.- 1 . It is prepared by (a) preparing a solution of Cabazitaxel in a suitable solvent and mixture thereof; and (b) recovering the Amorphous Forms of Cabazitaxel from the solution thereof by removal of the solvent.

FIELD OF THE INVENTION

The present invention relates to the Amorphous Form of4-acetoxy-2α-benzoyloxy-5β-20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotan-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate, i.eCabazitaxel, methods for its preparation and pharmaceutical compositionthereof.

BACK GROUND OF THE INVENTION

Cabazitaxel, chemically known as4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotax-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-propionate,is represented by formula (I).

It is a microtubule inhibitor, indicated in combination with prednisonefor treatment of patients with hormone-refractory metastatic prostatecancer previously treated with a docetaxel-containing treatment regimen,under the trade name Jevtana®.

Cabazitaxel is known from U.S. Pat. No. 5,847,170. Process forpreparation of Cabazitaxel as described in U.S. Pat. No. 5,847,170involves column chromatography, which is cumbersome tedious and notcommercially viable.

The acetone solvate of 4-acetoxy-2α-benzoyloxy-5β-20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotan-11-en-13α-yl-(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate(Form A) is formed by crystallization by using acetone and ischaracterized by XRD in U.S. Pat. No. 7,241,907.

U.S. 20110144362 describes anhydrous crystalline Forms B to Form F,ethanolates Form B, D, E and F and mono and dihydrate Forms ofCabazitaxel. All the anhydrous crystalline forms are prepared either byacetone solvate or ethanol solvate. Mono and dihydrate forms are formedat ambient temperature in an atmosphere containing 10 and 60% relativehumidity, respectively.

From the above mentioned references it is evident that pure polymorphicform of Cabazitaxel prepared in the literature has been prepared bysolvates and not directly from Cabazitaxel.

None of literature reported earlier mentions about the Amorphous form ofCabazitaxel. Present invention provides novel form of Cabazitaxel i.e.Amorphous

Cabazitaxel obtained, which is directly obtained from the crudeCabazitaxel without formation of any solvate or hydrate of Cabazitaxel.

SUMMARY OF THE INVENTION

In the first aspect, there is provided an Amorphous form of Cabazitaxel.

In the second aspect, there is provided a process for preparation ofAmorphous form of Cabazitaxel comprising the steps of:

-   -   a) preparing a solution of Cabazitaxel in a suitable solvent and        mixture thereof; and    -   b) recovering the Amorphous Forms of Cabazitaxel from the        solution thereof by removal of the solvent.

In another aspect, there is provided a pharmaceutical composition thatincludes a therapeutically effective amount of an Amorphous form ofCabazitaxel and one or more Pharmaceutically acceptable carriers,excipients or diluents.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

FIG. 1, which represents the X-ray (powder) diffraction pattern of theAmorphous form of Cabazitaxel of the present invention

FIG. 2, which represents the Differential Scanning calorimetry (DSC)analysis for the Amorphous form of Cabazitaxel of the present invention

DETAILED DESCRIPTION OF THE INVENTION

The Amorphous form of Cabazitaxel may be characterized by XRD asdepicted in FIG.-1.

The Amorphous form of Cabazitaxel is totally and completely devoid ofany signal due to a crystalline form, in its X-ray (powder) diffractionpattern.

4-acetoxy-2α-benzoyloxy-5β-20-epoxy-1-hydroxy-7β,10β-dimethoxy-9-oxotan-11-en-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate i.e.,Cabazitaxel used as starting material, may be prepared according to themethod known in art such as described in U.S. Pat. No. 5,847,170.

In general, the solution of Cabazitaxel may be obtained by dissolvingCabazitaxel in suitable Solvent.

The suitable solvent may be selected from the group comprising ofalcohols, such as methanol, ethanol and isopropanol; nitriles, such asacetonitrile; chlorinated hydrocarbons, such as methylene chloride,ethylene dichloride; esters, such as ethyl acetate and isopropylacetate; cyclic ethers, such as dioxane and tetrahydrofuran and mixturesthereof. Most preferred solvent is methylene chloride.

The volume of the solvent, that can be used in step a) depends on thepolarity and the solubilizing capacity of the solvent and typically canbe employed in the range of between 2 to 100 times by volume per gram ofCabazitaxel.

The solution of Cabazitaxel in suitable solvent may be obtained atambient temperature.

Removal of solvent may include one or more distillation, distillationunder vacuum, evaporation, spray drying and freeze drying.

The temperature at which the solvent is removed depends on the solventemployed and generally can be from about 20° C. to about 200° C.

After evaporation of the solvent, the residual solid may optionally betreated with an organic solvent. Organic solvent may be selected fromthe hydrocarbon such as hexane, heptane, toluene and benzene.

The Amorphous form of Cabazitaxel may be recovered from the solutionusing a spray drying technique. A mini-Spray dryer (Model: Labultima(LU228) can be used. Labultima (LU228) Mini-Spray Dryer operates on theprinciple of nozzle spraying in a parallel flow, i.e the sprayed productand the drying gas flow in the same direction. The drying gas can be airor inert gases such as nitrogen, argon and carbon dioxide.

The air inlet temperature of the spray drier can be from about 40° C. toabout 100° C.

After removal of the solvent the process may include drying of theresidual solid in a drying oven.

The resulting Amorphous form of Cabazitaxel may be formulated intoordinary dosage forms such as, for example, tablets, capsules, pills,solutions, etc. In these cases, the medicaments can be prepared byconventional methods with conventional pharmaceutical excipients. Inaddition to the common dosage forms set out above, the Amorphous form ofCabazitaxel may also be administered by controlled release means and/ordelivery devices.

Further, the Amorphous Cabazitaxel described herein can be used in amethod for treatment of hormone-refractory metastatic prostate cancer.The method of treatment includes administering to a mammal in need oftreatment a dosage form that includes a therapeutically effective amountof the Amorphous form of Cabazitaxel.

The methods for the preparation of the Amorphous Form of Cabazitaxel ofthe present invention may be illustrated by way of the followingexamples, which in no way should be construed as limiting the scope ofthe invention.

EXAMPLE 1

2.0 g of Cabazitaxel was dissolved in 20 ml of Dichloromethane andconcentrated at 35-40° C. under vacuum to get solid product. Product wasfurther dried for 1 h at 35-40° C. under vacuum. Crude product wasstirred with 40 ml n-Hexane at room temperature for 15-20 min andfiltered. Obtained solid material was washed with 40 ml n-Hexane anddried for 6-7 hrs at 50-55° C. under reduced pressure.

EXAMPLE-2

2.0 g of Cabazitaxel was dissolved in 20 ml of Dichloromethane. Thesolution was then filtered through 0.5 micron filter and filtrate wasspray dried for 6 hrs at 40-45° C. to get Amorphous Cabazitaxel.

1. An Amorphous Form of Cabazitaxel.
 2. The Amorphous Form ofCabazitaxel of claim 1, characterized by an X-ray powder diffraction(XRD) pattern as depicted in FIG.-1.
 3. The Amorphous Form of claim 1,characterized by a melting endotherm of 132.87° C. as measured bydifferential scanning calorimetry.
 4. A process for preparing theAmorphous Form of Cabazitaxel of claim 1, which comprises: (a) preparinga solution of Cabazitaxel in a suitable solvent and mixture thereof; and(b) recovering the Amorphous Forms of Cabazitaxel from the solutionthereof by removal of the solvent.
 5. The process of claim 4, whereinthe solvent is selected from the group comprising alcohols, nitriles,chlorinated hydrocarbons, esters, cyclic ethers, and mixtures thereof.6. The process of claim 4, wherein the solvent is chlorinatedhydrocarbon.
 7. The process of claim 4, wherein the solvent isDichloromethane.
 8. The process of claim 4, wherein the Amorphous formis recovered from the solution using a spray drying technique.